Evolution of renal function during treatment with direct antiviral agents (DAA-t) in HIV/HCV infected patients in ICONA/HepaIcona cohorts

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1 Evolution of renal function during treatment with direct antiviral agents (DAA-t) in HIV/HCV infected patients in ICONA/HepaIcona cohorts Antonella Cingolani 1, Laura Galli 2, Giuseppe Lapadula 3, Stefano Bonora 4, Caterina Uberti Foppa 2, Antonio Di Biagio 5, Gabriella Verucchi 6, Silvia Odolini 7, Cristina Mussini 8, Andrea Antinori 9, Antonella d'arminio Monforte 10, Mauro Zaccarelli 8 for Icona Foundation Study Group 1 Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Policlinico Gemelli, Rome, Italy; 2 Department of Infectious Diseases, San Raffaele Scientific Institute, University Vita-Salute San Raffaele, Milan, Italy; 3 Division of Infectious Diseases, ASST Monza-Brianza- San Gerardo Hospital, Monza, Italy. 4 Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Amedeo di Savoia Hospital, 5 Unit of Infectious Diseases, IRCCS San Martino Hospital-IST, Genoa, Italy. 6 Unit of Infectious Diseases, S.Orsola-Malpighi Hospital, "Alma Mater Studiorum" University of Bologna,Bologna, Italy; 7 University Department of Infectious and Tropical Diseases, Spedali Civili General Hospital, Brescia, Italy 8 Infectious Disease Clinic, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy. 9 HIV/AIDS Department, INMI L. Spallanzani IRCCS, Rome, Italy; 10 ASST Santi Paolo e Carlo, University of Milan, Clinic of Infectious and Tropical Diseases, Department of Health Sciences, Milan, Italy.

2 BACKGROUND Eradication of HCV after therapy with interferon plus ribavirin in HIV/HCV-coinfected patients is associated not only with a reduction in liver-related events but also with a reduction in HIV progression and mortality not related to liver disease (Berenguer, Clin Infect Dis 2012). HCV-HIV patients had a 50-75% increased risk of CKD compared with HIV patients (Mocroft, AIDS 2007; Wyatt, AIDS 2008). Successful HCV treatment seems to slightly reduce the incidence of chronic kidney diseases (Kovari, Clin Infect Dis 2017). Concomitant treatment with ledipasvir/sofosbuvir and tenofovir has been reported as detrimental on kidney function (Bunnell, Pharmacother 2016).

3 OBJECTIVES In HIV/HCV co-infected patients, we aimed to assess: - changes in renal function (egfr) during and after treatment with direct acting antiviral drug (DAA) treatment, - factors associated with egfr changes during and after DAA treatment.

4 METHODS HIV/HCV patients from the ICONA/Hepaicona Cohort in active follow-up after January 2013 (N=3012) : Treated with DAA (February December 2016); With at least 12 weeks follow-up after the end of DAA treatment (SVR12); With regular egfr determinations (CKD-EPI formula) during and after DAA treatment [median number of egfr determinations on the overall follow-up: 6 (IQR: 3-8); during DAA: 3 (IQR: 1-4); post DAA: 3 (2-4)]. Follow-up accrued from the date of DAA start (baseline, within 3 months) to the date of last visit after the end of DAA treatment.

5 STATISTICAL ANALYSIS Patients were stratified by baseline egfr : <60 ml/min/1.73m 2, ml/min/1.73m 2, >90 ml/min/1.73m 2. Baseline characteristics of subjects with different baseline egfr values compared using chi-square and Kruskal-Wallis test. Mixed linear models with random intercept and slope fitted to: estimate mean egfr changes (slopes) from baseline at different time points [end of DAA treatment (EOT), at SVR12, at the end of follow-up]; identify factors associated with egfr changes (slopes) on the overall follow-up.

6 RESULTS Characteristics at DAA start (1) Overall egfr <60* egfr 60-90* egfr >90* (n=394) (n=16) (n=112) (n=266) P-value Age (years) Median (IQR) 53 (50-55) 52.5 ( ) 53 ( ) 52 (50-55) Gender Male 308 (78%) 11 (69%) 84 (75%) 213 (80%) Previous AIDS 65 (17%) 5 (31%) 23 (21%) 37 (14%) Nadir CD4+ (cells/µl) Median (IQR) 159 (70-254) 45 (20-78) 128 (52-190) 180 (81-275) Years of ART Median (IQR) 17.1 ( ) 15.7 ( ) 17.6 ( ) 17.1 ( ) Diabetes 24 (9%) 1 (6%) 17 (15%) 24 (9%) Hypertension 104 (26%) 10 (63%) 35 (31%) 59 (22%) Cirrhosis 172 (44%) 5 (32%) 47 (42%) 120 (45%) Previous kidney disease 26 (7%) 7 (44%) 8 (7%) 11 (4%) < * by CKD-EPI formula (ml/min/1.73m 2 )

7 RESULTS Characteristics at DAA start (2) Overall (n=394) egfr <60* (n=16) egfr 60-90* (n=112) egfr >90* (n=266) P-value PI-including regimens 132 (34%) 6 (38%) 36 (32%) 90 (34%) INSTI-including regimens 215 (55%) 10 (63%) 63 (56%) 142 (53%) TDF-includign regimens 264 (68%) 9 (56%) 74 (66%) 181 (69%) BL CD4+ (cells/µl) Median (IQR) 562 ( ) 450 ( ) 527 ( ) 573 ( ) BL HIV-RNA <50 cps/ml 358 (94%) 16 (100%) 101 (93%) 242 (95%) BL egfr* (ml/min/1.73m 2 ) Median (IQR) 99 (85 105) 57 (50-58) 79 (72-85) 103 (99 108) < HCV genotype 1/1a 177 (46%) 7 (44%) 47 (44%) 123 (48%) b 55 (15%) 2 (13%) 22 (21%) 31 (12%) 3 77 (20%) 4 (25%) 16 (15%) 57 (22%) 4 67 (18%) 3 (19%) 22 (21%) 42 (16%) Other/Mixed 4 (1.1%) 0 (0%) 0 (0%) 4 (1.4%) * by CKD-EPI formula (ml/min/1.73m 2 )

8 RESULTS Characteristics at DAA start (3) Overall egfr <60* egfr 60-90* egfr >90* (n=394) (n=16) (n=112) (n=266) P-value BL Stiffness (Kpa) Median (IQR) 14 (10-23) 11 (9-16) 14 (10-23) 14 (10-23) Type of DAA regimen LDV/SOF 117 (30%) 4 (25%) 40 (36%) 73 (27%) SOF-including 170 (43%) 7 (44%) 46 (41%) 117 (44%) SOF-sparing 107 (27%) 5 (31%) 26 (23%) 76 (29%) Use of ribavirin 268 (68%) 11 (69%) 66 (59%) 191 (72%) Previously treated with IFN/RBV 196 (50%) 11 (69%) 50 (45%) 135 (51%) SVR (93%) 12 (86%) 95 (90%) 230 (95%) * by CKD-EPI formula (ml/min/1.73m 2 )

9 Results - egfr changes over time and slopes ALL subjects (n=394) Overall median follow-up: 12.9 months (IQR: ) OVERALL FOLLOW-UP Mean egfr* change (slope) from baseline (95% Confidence Interval) (ml/min/1.73m2 per month) P-value (-0.44, -0.28) <.0001 During DAA EOT (-0.58, -0.21) <.0001 Post DAA 12W (-0.37, -0.14) < W (-0.55, -0.30) <.0001 Excluded subjects on DVG,RPV,cobi (n=299) OVERALL FOLLOW-UP * by CKD-EPI formula (ml/min/1.73m 2 ) Mean egfr* change (slope) from baseline (95% Confidence Interval) (ml/min/1.73m2 per month) P-value (-0.43, -0.25) <.0001 During DAA EOT (-0.64, -0.16) Post DAA 12W (-0.53, -0.23) < W (-0.76, -0.42) <.0001

10 Results - egfr changes over time and slopes according to baseline egfr Baseline egfr* Mean egfr* change (slope) from baseline (95% Confidence Interval) (ml/min/1.73m2 per month) OVERALL FOLLOW-UP EOT 12W post EOT <60 (n=16) 0.07 (-0.33, 0.46) P= (-1.70, -0.24) P= (0.03, 1.20) P= (n=112) (-0.30, 0.02) P= (0.02, 0.58) P= (-0.02, 0.38) P=0.082 >90 (n=266) (-0.59, -0.40) P< (-1.05, -0.54) P< (-0.66, -0.38) P<.0001 * by CKD-EPI formula (ml/min/1.73m 2 )

11 Results - egfr changes over time and slopes according to DAA regimen Type of DAA regimen LDV/SOF (n=45) LDV/SOF+TDF (n=72) SOF (n=53) SOF+TDF (n=115) Non-SOF (n=29) Non-SOF+TDF (n=77) Mean egfr* change (slope) from baseline (95% Confidence Interval) (ml/min/1.73m2 per month) OVERALL FOLLOW-UP (-0.55, -0.02) P= (-0.74, -0.32) p< (-0.70, -0.28) P< (-0.44, -0.16) P< (-0.45, 0.14) P= (-0.52, -0.17) P= * by CKD-EPI formula (ml/min/1.73m 2 ) EOT (-0.73, 0.41) P= (-1.06, -0.31) P= (-1.18, -0.11) P= (-0.68, -0.03) P= (-1.30, 0.85) P= (-0.63, 0.34) P= W post EOT (-0.75, -0.07) P= (-0.77, -0.24) P= (-0.64, -0.01) P= (-0.23, 0.19) P= (-0.71, 0.28) P= (-0.52, 0.03) P=0.081

12 Results - Factors associated with egfr changes over time The adjusted mean change in egfr on the overall follow-up was ml/min/1,73m 2 (95%CI: -0.37, -0.18), p< Characteristic Adjusted* difference in egfr change (95% Confidence Interval) (ml/min/1.73m2 per month) P-value Age (per year older) (-0.41/-0.05) Diabetes (yes vs no) (-6.09/ -0.80) Type of DAA regimen LDV/SOF (-3.44/ +1.26) SOF (-3.12/ +1.54) non-sof Ref Use of tenofovir (yes vs no) (-3.59/ +0.16) Baseline egfr (ml/min/1.73m 2 ) < < (+0.51/ ) (+3.19/ +7.08) <.0001 >90 Ref * Adjusted also for Nadir CD4+, HCV genotype (1/1a vs other), Years of ART, Use of ribavirin in the DAA regimen, Baseline CD4+, Cirrhosis.

13 LIMITATIONS The egfr decline prior to DAA treatment was not accounted for when considering egfr changes. The analysis of the relationship between DAA regimens and TDF use may have been impaired by a limited number of available subjects. The impact of drugs other than cart concomitantly administered could not be ruled out

14 CONCLUSIONS A slight overall reduction of renal function was observed during DAA treatment. Baseline egfr may determine different trajectories, leading to improvement in pts with more impaired baseline kidney function and to worsening in pts with higher baseline egfr. The concomitant use of TDF, independently of DAA regimens, tended to negatively affect renal function during DAA. Age and metabolic comorbidities seem to have a more detrimental role than concomitant potentially nephrotoxic drugs in renal function during DAA treatment.

15 ICONA Foundation Study Group BOARD OF DIRECTORS A d Arminio Monforte (President), A Antinori, A Castagna, F Castelli, R Cauda, G Di Perri, M Galli, R Iardino, G Ippolito, A Lazzarin, GC Marchetti, CF Perno, G Rezza, F von Schloesser, P Viale. SCIENTIFIC SECRETARY A d Arminio Monforte, A Antinori, A Castagna, F Ceccherini-Silberstein, A Cozzi-Lepri, E Girardi, S Lo Caputo, C Mussini, M Puoti. STEERING COMMITTEE M Andreoni, A Ammassari, A Antinori, C Balotta, A Bandera, P Bonfanti, S Bonora, M Borderi, A Calcagno, L Calza, MR Capobianchi, A Castagna, F Ceccherini- Silberstein, A Cingolani, P Cinque, A Cozzi-Lepri, A d Arminio Monforte, A De Luca, A Di Biagio, E Girardi, N Gianotti, A Gori, G Guaraldi, G Lapadula, M Lichtner, S Lo Caputo, G Madeddu, F Maggiolo, G Marchetti, S Marcotullio, L Monno, C Mussini, S Nozza, M Puoti, E Quiros Roldan, R Rossotti, S Rusconi, MM Santoro, A Saracino, M Zaccarelli. STATISTICAL AND MONITORING TEAM A Cozzi-Lepri, I Fanti, L Galli, P Lorenzini, A Rodano, M Shanyinde, A Tavelli. BIOLOGICAL BANK INMI F Carletti, S Carrara, A Di Caro, S Graziano, F Petrone, G Prota, S Quartu, S Truffa. PARTICIPATING PHYSICIANS AND CENTERS Italy A Giacometti, A Costantini, V Barocci (Ancona); G Angarano, L Monno, C Santoro (Bari); F Maggiolo, C Suardi (Bergamo); P Viale, V Donati, G Verucchi (Bologna); F Castelli, C Minardi, E Quiros Roldan (Brescia); T Quirino, C Abeli (Busto Arsizio); PE Manconi, P Piano (Cagliari); B Cacopardo, B Celesia (Catania); J Vecchiet, K Falasca (Chieti); L Sighinolfi, D Segala (Ferrara); P Blanc, F Vichi (Firenze); G Cassola, C Viscoli, A Alessandrini, N Bobbio, G Mazzarello (Genova); C Mastroianni, I Pozzetto (Latina); P Bonfanti, I Caramma (Lecco); A Chiodera, P Milini (Macerata); G Nunnari, G Pellicanò (Messina); A d Arminio Monforte, M Galli, A Lazzarin, G Rizzardini, M Puoti, A Castagna, G Marchetti, MC Moioli, R Piolini, AL Ridolfo, S Salpietro, C Tincati, (Milano); C Mussini, C Puzzolante (Modena); A Gori, G Lapadula (Monza); A Chirianni, G Borgia, V Esposito, R Orlando, G Bonadies, F Di Martino, I Gentile, L Maddaloni (Napoli); AM Cattelan, S Marinello (Padova); A Cascio, C Colomba (Palermo); F Baldelli, E Schiaroli (Perugia); G Parruti, F Sozio (Pescara); G Magnani, MA Ursitti (Reggio Emilia); M Andreoni, A Antinori, R Cauda, A Cristaudo, V Vullo, R Acinapura, G Baldin, M Capozzi, S Cicalini, A Cingolani, L Fontanelli Sulekova, G Iaiani, A Latini, I Mastrorosa, MM Plazzi, S Savinelli, A Vergori (Roma); M Cecchetto, F Viviani (Rovigo); G Madeddu, P Bagella (Sassari); A De Luca, B Rossetti (Siena); A Franco, R Fontana Del Vecchio (Siracusa); D Francisci, C Di Giuli (Terni); P Caramello, G Di Perri, S Bonora, GC Orofino, M Sciandra (Torino); M Bassetti, A Londero (Udine); G Pellizzer, V Manfrin (Vicenza); G Starnini, A Ialungo(Viterbo). Funding: ICONA Foundation is supported by unrestricted grants from Bristol Myers Squibb, Gilead Science, Janssen, Merck Sharpe and Dohme and ViiV Healthcare Italy.